This invention relates to aryl fused azapolycyclic compounds, as defined more specifically by formula I below. Compounds of formula I bind to neuronal nicotinic acetylcholine specific receptor sites and are useful in modulating cholinergic function. Such compounds are useful in the treatment of inflammatory bowel disease (including but not limited to ulcerative colitis, pyoderma gangrenosum and Crohn""s disease), irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, celiac sprue, pouchitis, vasoconstriction, anxiety, panic disorder, depression, bipolar disorder, autism, sleep disorders, jet lag, amyotrophic lateral sclerosis (ALS), cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrhythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supranuclear palsy, chemical dependencies and addictions (e.g., dependencies on, or addictions to nicotine (and/or tobacco products), alcohol, benzodiazepines, barbiturates, opioids or cocaine), headache, migraine, stroke, traumatic brain injury (TBI), obsessive-compulsive disorder (OCD), psychosis, Huntington""s chorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multi-infarct dementia, age-related cognitive decline, epilepsy, including petit mal absence epilepsy, senile dementia of the Alzheimer""s type (AD), Parkinson""s disease (PD), attention deficit hyperactivity disorder (ADHD) and Tourette""s Syndrome.
The compounds of this invention may also be used in combination with an antidepressant such as, for example, a tricyclic antidepressant or a serotonin reuptake inhibiting antidepressant (SRI), in order to treat both the cognitive decline and depression associated with AD, PD, stroke, Huntington""s chorea or traumatic brain injury (TBI); in combination with muscarinic agonists in order to stimulate both central muscarinic and nicotinic receptors for the treatment, for example, of ALS, cognitive dysfunction, age-related cognitive decline, AD, PD, stroke, Huntington""s chorea and TBI; in combination with neurotrophic factors such as NGF in order to maximize cholinergic enhancement for the treatment, for example, of ALS, cognitive dysfunction, age-related cognitive decline, AD, PD stroke, Huntington""s chorea and TBI; or in combination with agents that slow or arrest AD such as cognition enhancers, amyloid aggregation inhibitors, secretase inhibitors, tau kinase inhibitors, neuronal anti-inflammatory agents and estrogen-like therapy.
Other compounds that bind to neuronal nicotinic receptor sites are referred to in U.S. patent application Ser. No. 08/963,852, which was filed on Nov. 4, 1997. The foregoing application is owned in common with the present application, and is incorporated herein by reference in its entirety.
This invention relates to aryl fused azapolycyclic compounds of the formula 
R1 is hydrogen, (C1-C6)alkyl, unconjugated (C3-C6)alkenyl, benzyl, XC(xe2x95x90O)R13 or xe2x80x94CH2CH2xe2x80x94Oxe2x80x94(C1-C4)alkyl;
R2 and R3 are selected, independently, from hydrogen, (C2-C6)alkenyl, (C2-C6)alkynyl, hydroxy, nitro, amino, halo, cyano, xe2x80x94SOq(C1-C6)alkyl wherein q is zero, one or two, (C1-C6)alkylamino-, [(C1-C6)alkyl]2amino-, xe2x80x94CO2R4, xe2x80x94CONR5R6, xe2x80x94SO2NR7R8, xe2x80x94C(xe2x95x90O)R13, xe2x80x94XC(xe2x95x90O)R13, wherein said aryl is selected from phenyl and naphthyl, heteroaryl-(C0-C3)alkyl- or heteroaryl-(C0-C3)alkyl-Oxe2x80x94, wherein said heteroaryl is selected from five to seven membered aromatic rings containing from one to four heteroatoms selected from oxygen, nitrogen and sulfur; X2(C0-C6)alkyl- and X2(C1-C6)alkoxy-(C0-C6)alkyl-, wherein X2 is absent or X2 is (C1-C6)alkylamino- or [(C1-C6)alkyl]2amino-, and wherein the (C0-C6)alkyl- or (C1-C6)alkoxy-(C0-C6)alkyl- moieties of said X2(C0-C6)alkyl- or X2(C1-C6)alkoxy-(C0-C6)alkyl- contains at least one carbon atom, and wherein from one to three of the carbon atoms of said (C0-C6)alkyl- or (C1-C6)alkoxy-(C0-C6)alkyl- moieties may optionally be replaced by an oxygen, nitrogen or sulfur atom, with the proviso that any two such heteroatoms must be separated by at least two carbon atoms, and wherein any of the alkyl moieties of said (C0-C6)alkyl- or (C1-C6)alkoxy-(C0-C6)alkyl-groups may be optionally substituted with from two to seven fluorine atoms, and wherein one of the carbon atoms of each of the alkyl moieties of said aryl-(C0-C3)alkyl- and said heteroaryl-(C0-C3)alkyl- may optionally be replaced by an oxygen, nitrogen or sulfur atom, and wherein each of the foregoing aryl and heteroaryl groups may optionally be substituted with one or more substituents, preferably from zero to two substituents, independently selected from (C1-C6)alkyl optionally substituted with from one to seven fluorine atoms, (C1-C6)alkoxy optionally substituted with from two to seven fluorine atoms, halo (e.g., chloro, fluoro, bromo or iodo), (C2-C6)alkenyl, (C2-C6)alkynyl, hydroxy, nitro, cyano, amino, (C1-C6)alkylamino-, [(C1-C6)alkyl]2amino-, xe2x80x94CO2R4, xe2x80x94CONR5R6, xe2x80x94SO2NR7R8, xe2x80x94C(xe2x95x90O)R13 and xe2x80x94XC(xe2x95x90O)R13;
or R2 and R3, together with the carbons to which they are attached, form a four to seven membered monocyclic, or a ten to fourteen membered bicyclic, carbocyclic ring that can be saturated or unsaturated, wherein from one to three of the non-fused carbon atoms of said monocyclic rings, and from one to five of the carbon atoms of said bicyclic rings that are not part of the benzo ring shown in formula I, may optionally and independently be replaced by a nitrogen, oxygen or sulfur, and wherein said monocyclic and bicyclic rings may optionally be substituted with one or more substituents, preferably from zero to two subsbtuents for the monocyclic rings and from zero to three substituents for the bicyclic rings, that are selected, independently, from (C0-C6)alkyl- or (C1-C6)alkoxy-(C0-C6)alkyl-, wherein the total number of carbon atoms does not exceed six and wherein any of the alkyl moieties may optionally be substituted with from one to seven fluorine atoms; nitro, oxo, cyano, halo, (C2-C6)alkenyl, (C2-C6)alkynyl, hydroxy, amino, (C1-C6)alkylamino-, [(C1-C6)alkyl]2amino-, xe2x80x94CO2R4, xe2x80x94CONR5R6, xe2x80x94SO2NR7R8, xe2x80x94C(xe2x95x90O)R13, and xe2x80x94XC(xe2x95x90O)R13;
each R4, R5, R6, R7, R8 and R13 is selected, independently, from hydrogen and (C1-C6)alkyl, or R5 and R6, or R7 and R8 together with the nitrogen to which they are attached, form a pyrrolidine, piperidine, morpholine, azetidine, piperazine, xe2x80x94Nxe2x80x94(C1-C6)alkylpiperazine or thiomorpholine ring, or a thiomorpholine ring wherein the ring sulfur is replaced with a sulfoxide or sulfone; and
each X is, independently, (C1-C6)alkylene;
with the proviso that: (a) at least one of R1, R2 and R3 must be the other than hydrogen, and (b) when R2 and R3 are hydrogen, R1 cannot be hydrogen, (C1-C6)alkyl, or unconjugated (C3-C6)alkenyl, and pharmaceutically acceptable salts of such compounds.
Examples of possible heteroaryl groups within the definition of R2 and R3 are the following: thienyl, oxazoyl, isoxazolyl, pyridyl, pyrimidyl, thiazolyl, tetrazolyl, isothiazolyl, triazolyl, imidazolyl, tetrazolyl, pyrrolyl and the following groups: 
wherein one of R9 and R18 is hydrogen or (C1-C6)alkyl, and the other is a bond to the benzo ring of formula I.
Examples of compounds of this invention are compounds of the formula I, and their pharmaceutically acceptable salts, wherein R2 and R3, together with the benzo ring of formula I, form a bicyclic ring system selected from the following: 
wherein R10 and R17 are selected, independently, from hydrogen, (C1-C6)alkyl; and (C1-C6)alkoxy-(C0-C6)alkyl- wherein the total number of carbon atoms does not exceed six and wherein any of the alkyl moieties may optionally be substituted with from one to seven fluorine atoms; nitro, cyano, halo, amino, (C1-C6)alkylamino-, [(C1-C6) alkyl]2amino-, xe2x80x94CO2R4, xe2x80x94CONR5R6, xe2x80x94SO2NR7R8, xe2x80x94C(xe2x95x90O)R13, xe2x80x94XC(xe2x95x90O)R13, phenyl and monocyclic heteroaryl wherein said heteroaryl is defined as R2 and R3 are defined in the definition of compounds of the formula I above;
Other embodiments of this invention relate to compounds of the formula I, and their pharmaceutically acceptable salts, wherein R2 and R3, together with the benzo ring of formula I, form a bicyclic or tricyclic ring system selected from the following: 
wherein R10 and R17 are defined as above, and m is zero, one or two, and wherein one of the carbon atoms of ring A can optionally be replaced with oxygen or N(C1-C6)alkyl.
Other embodiments of this invention relate to compounds of the formula I, and their pharmaceutically acceptable salts, wherein neither R2 nor R3 is attached to the benzo ring of formula I via an oxygen atom.
Other embodiments of this invention relate to compounds of the formula I, and their pharmaceutically acceptable salts, wherein R2 and R3 do not, together with the benzo ring of formula I, form a bicyclic or tricyclic ring system.
Other embodiments of this invention relate to compounds of the formula I wherein one or both of R2 and R3 are xe2x80x94C(xe2x95x90O)R13, wherein R13 is (C1-C6)alkyl. Further embodiments of this invention relate to compounds of the formula I wherein one or both of R2 and R3 are xe2x80x94C(xe2x95x90O)R13, wherein R13 is (C1-C6)alkyl or (C1-C3)alkyl optionally substituted with from one to seven fluorine atoms. Other embodiments relate to compounds of the formula I wherein one of R2 and R3 is CF3, fluoro, cyano, (C2-C6)alkynyl or C2F5.
Other further embodiments of the present invention relates to compounds of formula I having the structure 
wherein R1 is as defined above; and R2 and R3 are hydrogen, (C1-C6)alkyl optionally substituted with from one to seven fluorine atoms; xe2x80x94C(xe2x95x90O)(C1-C6)alkyl, cyano, hydroxy, nitro, amino, xe2x80x94O(C1-C6)alkyl or halo;
with the proviso that R2 and R3 can not both be hydrogen when R1 is hydrogen, (C1-C6)alkyl, or unconjugated (C3-C6)alkenyl.
Examples of specific compounds of the formula I are the following compounds, which, in the instances where there is a center or centers of asymmetry in the molecule, may comprise a racemic mixture or the single enantiomer:
5,13-diazatetracyclo[9.3.1.02,10.04,8]pentadeca-2,4(8),9-trien-6-one;
6-oxo-5-oxa-7,13-diazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,6,8-tetraene;
2-fluoro-N-(4-hydroxy-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-5-yl)-benzamide;
6-methyl-5-thia-7,13-diazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,6,8-tetraene;
6-methyl-7-propyl-5,7,13-triazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10), 3,5,8-tetraene;
5,7,13-triazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,5,8-tetraene;
7-methyl-5,7,13triazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,5,8-tetraene;
6-methyl-5,7,13-triazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,5,8-tetraene;
6,7-dimethyl-5,7,13-triazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,5,8-tetraene;
7-propyl-5,7,13-triazatetracyclo[9.3.1.02,10.04,8)pentadeca-2(10),3,5,8-tetraene;
7-butyl-5,7,13-triazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,5,8-tetraene;
6-methyl-7-isobutyl-5,7,13-triazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,5,8-tetraene;
7-phenyl-5,7,13-triazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,5,8-tetraene;
6-methyl-7-phenyl-5,7,13-triazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,5,8-tetraene;
7-neopentyl-5,7,13-triazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,5,8-tetraene;
6-methyl-7-neopentyl-5,7,13-triazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,5,8-tetraene;
6,7-dimethyl-5,8,14-triazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11),3,5,7,9-pentaene;
5,8,14-triazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11),3,5,7,9-pentaene;
14-methyl-5,8,14-triazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11),3,5,7,9-pentaene;
5-oxa-7,13-iazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,6,8-tetraene;
6-methyl-5-oxa-7,13-diazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,6,8-tetraene;
7-methyl-5-oxa-6,13-diazatetracyclo[9.3.1.02,10.04,8]pentadeca-2,4(8),6,9-tetraene;
4-methyl-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
4-nitro-10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
4-amino-10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
N1-[10-azatricyclo[6.3.1.02,7]dodeca-]2(7),3,5-trien-4-yl]acetamide;
4,5-dinitro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
4,5-difluoro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
4-chloro-10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
3-(10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-4-yl)-5-methyl-1,2,4-oxadiazole;
10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-4-ol;
4,5-dichloro-10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
N4,N4-dimethyl-10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene-4-sulfonamide;
4-(1-pyrrolidinylsulfonyl)-10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
1-(10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-4-yl)-1-ethanone;
3-trifluoromethyl-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
4-trifluoromethyl-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
3-fluoro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-4-yl cyanide;
4-fluoro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
5,14-diazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11),3,5,7,9-pentaene;
6-methyl-5,14-diazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11),3,5,7,9-pentaene;
7-methyl-5,14-diazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11),3,5,7,9-pentaene;
7ethyl-5,14-diazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11),3,5,7,9-pentaene;
8-methyl-5,14-diazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11),3,5,7,9-pentaene;
5,14diazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11),3,7,9-tetraen-6-one;
6-chloro-5,14-diazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11)),3,5,7,9-pentaene; 6-methoxy-5,14-diazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11),3,5,7,9-pentaene; 6-chloro-10-fluoro-5,14-diazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11),3,5,7,9-pentaene;
5,8,14-triazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11),3,7,9-tetraen-4-one;
6-chloro-3-fluoro-5,14-diazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11),3,5,7,9-pentaene;
and pharmaceutically acceptable salts thereof.
Other embodiments compounds of the invention include but are not limited to:
6-methyl-5,7-dioxo-6,13-diazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,8-triene;
6-methyl-5-oxo-6,13-diazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,8-triene;
5,7-dimethyl-6-oxo-5,7,13-triazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,8-triene;
5,7-dioxo-6,13-diazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,8-triene;
5-oxo-6,13-diazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,8-triene;
6-oxo-5,7,13-triazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,8-triene;
6-methyl-5-thia-5-dioxo-6,13-diazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,6,8-tetraene;
7-dimethylamino-5-thia-5-dioxo-6,13-diazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,6,8-tetraene;
6,7-dioxo-5,8,14-triazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11),3,9-triene;
5,8-dimethyl-6,7-dioxo-5,8,14-triazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11),3,9-triene;
5-oxa-7-methyl-6-oxo-7,13-diazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,8-triene;
5-fluoro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene-4-carbonitrile;
4-ethynyl-5-fluoro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
5ethynyl-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-4-carbonitrile;
5-chloro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene-4-carbonitrile;
4-ethynyl-5-chloro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
4-fluoro-5-trifluoromethyl-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
4-chloro-5-trifluoromethyl-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
5-trifluoromethyl-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene-4-carbonitrile;
4-ethynyl-5-trifluoromethyl-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
4,5-bistrifluoromethyl-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
and pharmaceutically acceptable salts thereof. Other embodiments of the invention are the hydrochloride salts of the above enumerated compounds.
This invention also relates to compounds of the formula 
wherein P is hydrogen, methyl, COOR16 wherein R16 is (C1-C6)alkyl, allyl, 2,2,2-trichloroethyl or (C1-C6)alkyl; xe2x80x94C(xe2x95x90O)NR5R6 wherein R5 and R6 are defined as in formula I above; xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)(C1-C6)alkyl wherein the alkyl moiety may optionally be substituted with from 1 to 3 halo atoms, preferably with from 1 to 3 fluoro or chloro atoms; benzyl or t-butoxycarbonyl (t-Boc); and R14 and R15 are selected, independently, from hydrogen, (C1-C6)alkyl optionally substituted with from one to seven fluorine atoms; xe2x80x94C(xe2x95x90O)(C1-C6)alkyl, cyano, hydroxy, nitro, amino, xe2x80x94O(C1-C6)alkyl or halo; with the proviso that R14 and R15 can not both be hydrogen when P is hydrogen, (C1-C6)alkyl, or unconjugated (C3-C6)alkenyl. Such compounds are useful as intermediates in the synthesis of compounds of the formula I.
The invention also relates to compounds of the formula: 
wherein R2 and R3 are defined above; and Pxe2x80x2 is COOR16 wherein R16 is allyl, 2,2,2-trichloroethyl or (C1-C6)alkyl; xe2x80x94C(xe2x95x90O)NR5R6 wherein R5 and R6 are also as defined above; xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)(C1-C6)alkyl wherein the alkyl moiety may optionally be substituted with from 1 to 3 halo atoms, preferably with from 1 to 3 fluoro or chloro atoms; benzyl, or t-butoxycarbonyl.
Unless otherwise indicated, the term xe2x80x9chaloxe2x80x9d, as used herein, includes fluoro, chloro, bromo and iodo.
Unless otherwise indicated, the term xe2x80x9calkylxe2x80x9d, as used herein, includes straight chain moieties, and where the number of carbon atoms suffices, branched and cyclic moieties.
The term xe2x80x9calkoxyxe2x80x9d, as used herein, means xe2x80x9cxe2x80x94O-alkylxe2x80x9d or xe2x80x9calkyl-Oxe2x80x94xe2x80x9d, wherein xe2x80x9calkylxe2x80x9d is defined as above.
The term xe2x80x9calkylene, as used herein, means an alkyl radical having two available bonding sites (i.e., -alkyl-), wherein xe2x80x9calkylxe2x80x9d is defined as above.
Unless otherwise indicated, the term xe2x80x9cone or more substituentsxe2x80x9d, as used herein, refers to from one to the maximum number of substituents possible based on the number of available bonding sites.
The term xe2x80x9ctreatmentxe2x80x9d, as used herein, refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such condition or disorder. The term xe2x80x9ctreatmentxe2x80x9d, as used herein, refers to the act of treating, as xe2x80x9ctreatingxe2x80x9d is defined immediately above.
The compounds of formula I may have optical centers and therefore may occur in different enantiomeric configurations. The invention includes all enantiomers, diastereomers, and other stereoisomers of such compounds of formula I, as well as racemic and other mixtures thereof.
Particularly, preferred enantiomers of the invention include:
(+)-5,13-diazatetracyclo[9.3.1.02,10.04,8]pentadeca-2,4(8),9-trien-6-one;
(+)-6-oxo-5-oxa-7,13-diazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,6,8-tetraene;
(+)-2-fluoro-N-(4-hydroxy-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-5-yl)-benzamide;
(+)-6-methyl-5-thia-7,13-diazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,6,8-tetraene;
(+)-6-methyl-7-propyl-5,7,13-triazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,5,8-tetraene;
(+)-7-methyl-5,7,13-triazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,5,8-tetraene;
(+)-6,7-dimethyl-5,7,13-triazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,5,8-tetraene;
(+)-7-propyl-5,7,13-triazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,5,8-tetraene;
(+)-7-butyl-5,7,13-triazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,5,8-tetraene;
(+)-6-methyl-7-isobutyl-5,7,13-triazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,5,8-tetraene;
(+)-7-phenyl-5,7,13-triazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,5,8-tetraene;
(+)-6-methyl-7-phenyl-5,7,13-triazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,5,8-tetraene;
(+)-7-neopentyl-5,7,13-triazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,5,8-tetraene;
(+)-6-methyl-7-neopentyl-5,7,13-triazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,5,8-tetraene;
(+)-5-oxa-7,13-diazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,6,8-tetraene;
(+)-6-methyl-5-oxa-7,13-diazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,6,8-tetraene;
(+)-7-methyl-5-oxa-6,13-diazatetracyclo[9.3.1.02,10.04,8]pentadeca-2,4(8),6,9-tetraene;
(+)-4-methyl-10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
(+)-4-nitro-10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
(+)-4-amino-10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
(+)-N1-[10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-4-yl]acetamide;
(+)-4-chloro-10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
(+)-3-(10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-4-yl)-5-methyl-1,2,4-oxadiazole;
(+)-10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-4-ol;
(+)-N4,N4-dimethyl-10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene-4-sulfonamide;
(+)-4-(1-pyrrolidinylsulfonyl)-10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
(+)-1-(10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-4-yl)-1-ethanone;
(+)-3-trifluoromethyl-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
(+)-4-trifluoromethyl-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
(+)-3-fluoro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
(+)-10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-4-yl cyanide;
(+)-4-fluoro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
(+)-6-methyl-5-oxo-6,13-diazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,8-triene;
(+)-5-oxo-6,13-diazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,8-triene;
(+)-6-methyl-5-thia-5-dioxo-6,13-diazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,6,8-tetraene;
(+)-7-dimethylamino-5-thia-5-dioxo-6,13-diazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,6,8-tetraene;
(+)-5-oxa-7-methyl-6-oxo-7,13-diazatetracyclo[9.3.1.02.10.04,8]pentadeca-2(10),3,8-triene;
(+)-5-fluoro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene-4-carbonitrile;
(+)-4-ethynyl-5-fluoro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
(+)-5-ethynyl-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene-4-carbonitrile;
(+)-5-chloro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene-4-carbonitrile;
(+)-4-ethynyl-5-chloro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
(+)-4-fluoro-5-trifluoromethyl-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
(+)-4-chloro-5-trifluoromethyl-10-aza -tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
(+)-5-trifluoromethyl-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene-4-carbonitrile;
(+)-4-ethynyl-5-trifluoromethyl-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
(+)-5,14-diazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11),3,5,7,9-pentaene;
(+)-6-methyl-5,14-diazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11),3,5,7,9-pentaene;
(+)-7-methyl-5,14-diazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11),3,5,7,9-pentaene;
(+)-7-ethyl-5,14-diazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11),3,5,7,9-pentaene;
(+)-8-methyl-5,14-diazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11),3,5,7,9-pentaene;
(+)-5,14-diazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11),3,7,9-tetraen-6-one;
(+)-6-chloro-5,14-diazatetracyclo[10.3.1.02,11.04.9]hexadeca-2(11),3,5,7,9-pentaene;
(+)-6-methoxy-5,14-diazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11),3,5,7,9-pentaene;
(+)-6-chloro-10-fluoro-5,14-diazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11),3,5,7,9-pentaene;
(+)-5,8,14-triazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11),3,7,9-tetraen-6-one;
(+)-6-chloro-3-fluoro-5,14-diazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11),3,5,7,9-pentaene;
and pharmaceutically acceptable salts thereof.
In addition, other preferred enantiomers of the compounds of the invention include:
(xe2x88x92)-5,13-diazatetracyclo[9.3.1.02,10.04,8]pentadeca-2,4(8),9-trien-6-one;
(xe2x88x92)-6-oxo-5-oxa-7,13-diazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,6,8-tetraene;
(xe2x88x92)-2-fluoro-N-(4-hydroxy-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-5-yl)-benzamide;
(xe2x88x92)-6-methyl-5-thia-7,13-diazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,6,8-tetraene;
(xe2x88x92)-6-methyl-7-propyl-5,7,13-triazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,5,8-tetraene;
(xe2x88x92)-7-methyl-5,7,13-triazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,5,8-tetraene;
(xe2x88x92)-6,7-dimethyl-5,7,13-triazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,5,8-tetraene;
(xe2x88x92)-7-propyl-5,7,13-triazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,5,8-tetraene;
(xe2x88x92)-7-butyl-5,7,13-triazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,5,8-tetraene;
(xe2x88x92)-6-methyl-7-isobutyl-5,7,13-triazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,5,8-tetraene;
(xe2x88x92)-7-phenyl-5,7,13-triazatetracyclo[9.3.1.02.10.04,8]pentadeca-2(10),3,5,8-tetraene;
(xe2x88x92)-6-methyl-7-phenyl-5,7,13-triazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,5,8-tetraene;
(xe2x88x92)-7-neopentyl-5,7,13-triazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,5,8-tetraene;
(xe2x88x92)-6-methyl-7-neopentyl-5,7,13-triazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,5,8-tetraene;
(xe2x88x92)-5-oxa-7,13-diazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,6,8-tetraene;
(xe2x88x92)-6-methyl-5-oxa-7,13-diazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,6,8-tetraene;
(xe2x88x92)-7-methyl-5-oxa-6,13-diazatetracyclo[9.3.1.02,10.04,8]pentadeca-2,4(8),6,9-tetraene;
(xe2x88x92)-4-methyl-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
(xe2x88x92)-4-nitro-10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
(xe2x88x92)-4-amino-10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
(xe2x88x92)-N1-[10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-4-yl]acetamide;
(xe2x88x92)-4-chloro-10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
(xe2x88x92)-3-(10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-4-yl)-5-methyl-1,2,4-oxadiazole;
(xe2x88x92)-10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-4-ol;
(xe2x88x92)-N4,N4-dimethyl-10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene-4-sulfonamide;
(xe2x88x92)-4-(1-pyrrolidinylsulfonyl)-10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
(xe2x88x92)-1-(10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-4-yl)-1-ethanone;
(xe2x88x92)-3-trifluoromethyl-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
(xe2x88x92)-4-trifluoromethyl-10-aza-tricyclo[6.3.1.027]dodeca-2(7),3,5-triene;
(xe2x88x92)-3-fluoro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
(xe2x88x92)-10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-4-yl cyanide;
(xe2x88x92)-4-fluoro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
(xe2x88x92)-6-methyl-5-oxo-6,13-diazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,8-triene;
(xe2x88x92)-5-oxo-6,13-diazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,8-triene;
(xe2x88x92)-6-methyl-5-thia-5-dioxo-6,13-diazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,6,8-tetraene;
(xe2x88x92)-7-dimethylamino-5-thia-5-dioxo-6,13-diazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,6,8-tetraene;
(xe2x88x92)-5-oxa-7-methyl-6-oxo-7,13-diazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,8-triene;
(xe2x88x92)-5-fluoro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene-4-carbonitrile;
(xe2x88x92)-4-ethynyl-5-fluoro-10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
(xe2x88x92)-5-ethynyl-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene-4-carbonitrile;
(xe2x88x92)-5-chloro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene-4-carbonitrile;
(xe2x88x92)-4-ethynyl-5-chloro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
(xe2x88x92)-4-fluoro-5-trifluoromethyl-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
(xe2x88x92)-4-chloro-5-trifluoromethyl-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
(xe2x88x92)-5-trifluoromethyl-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5triene-4-carbonitrile;
(xe2x88x92)-4ethynyl-5-trifluoromethyl-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
(xe2x88x92)-5,14-diazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11),3,5,7,9-pentaene;
(xe2x88x92)-6-methyl-5,14-diazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11),3,5,7,9-pentaene;
(xe2x88x92)-7-methyl-5,14-diazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11),3,5,7,9-pentaene;
(xe2x88x92)-7-ethyl-5,14-diazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11),3,5,7,9-pentaene;
(xe2x88x92)-8-methyl-5,14-diazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11),3,5,7,9-pentaene;
(xe2x88x92)-5,14-diazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11),3,7,9-tetraen-6-one;
(xe2x88x92)-6-chloro-5,14-diazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11),3,5,7,9-pentaene;
(xe2x88x92)-6-methoxy-5,14-diazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11),3,5,7,9-pentaene;
(xe2x88x92)-6-chloro-10-fluoro-5,14-diazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11),3,5,7,9-pentaene;
(xe2x88x92)-5,8,14-triazatetracyclo[10.3.1.02.11.04,9]hexadeca-2(11),3,7,9-tetraen-4-one;
(xe2x88x92)-6-chloro-3-fluoro-5,14-diazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11),3,5,7,9-pentaene;
and pharmaceutically acceptable salts thereof.
The present invention also relates to all radiolabeled forms of the compounds of the formula I. Preferred radiolabeled compounds of formula I are those wherein the radiolabels are selected from as 3H, 11C, 14C, 18F, 123I and 125I. Such radiolabeled compounds are useful as research and diagnostic tools in metabolism studies, such as pharmacokinetics studies, etc., and in binding assays in both animals and man.
The present invention also relates to a pharmaceutical composition for use in reducing nicotine addiction or aiding in the cessation or lessening of tobacco use in a mammal, including a human, comprising an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, that is effective in reducing nicotine addiction or aiding in the cessation or lessening of tobacco use and a pharmaceutically acceptable carrier.
The present invention also relates to a method for reducing nicotine addiction or aiding in the cessation or lessening of tobacco use in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, that is effective in reducing nicotine addiction or aiding in the cessation or lessening of tobacco use.
The present invention also relates to a method of treating a disorder or condition selected from inflammatory bowel disease (including but not limited to ulcerative colitis, pyoderma gangrenosum and Crohn""s disease), irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, celiac sprue, pouchitis, vasoconstriction, anxiety, panic disorder, depression, bipolar disorder, autism, sleep disorders, jet lag, amyotrophic lateral sclerosis (ALS), cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrhythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supranuclear palsy, chemical dependencies and addictions (e.g., dependencies on, or addictions to nicotine (and/or tobacco products), alcohol, benzodiazepines, barbiturates, opioids or cocaine), headache, migraine, stroke, traumatic brain injury (TBI), obsessive-compulsive disorder (OCD), psychosis, Huntington""s chorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multi-infarct dementia, age-related cognitive decline, epilepsy, including petit mal absence epilepsy, senile dementia of the Alzheimer""s type (AD), Parkinson""s disease (PD), attention deficit hyperactivity disorder (ADHD) and Tourette""s Syndrome in a mammal, comprising administering to a mammal in need of such treatment an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder or condition.
The present invention also relates to a pharmaceutical composition for treating a disorder or condition selected from inflammatory bowel disease (including but not limited to ulcerative colitis, pyoderma gangrenosum and Crohn""s disease), irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, celiac sprue, pouchitis, vasoconstriction, anxiety, panic disorder, depression, bipolar disorder, autism, sleep disorders, jet lag, amyotrophic lateral sclerosis (ALS), cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrhythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supranuclear palsy, chemical dependencies and addictions (e.g., dependencies on, or addictions to nicotine (and/or tobacco products), alcohol, benzodiazepines, barbiturates, opioids or cocaine), headache, migraine, stroke, traumatic brain injury (TBI), obsessive-compulsive disorder (OCD), psychosis, Huntington""s chorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multi-infarct dementia, age-related cognitive decline, epilepsy, including petit mal absence epilepsy, senile dementia of the Alzheimer""s type (AD), Parkinson""s disease (PD), attention deficit hyperactivity disorder (ADHD) and Tourette""s Syndrome in a mammal, comprising an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceable carrier.
The present invention also relates to a method for reducing nicotine addiction or aiding in the cessation or lessening of tobacco use in a mammal, comprising administering to said mammal an amount of a compound comprising an amount of a compound of the formula 
wherein R19 is selected from the group consisting of hydrogen, (C1-C6)alkyl, or unconjugated (C3-C6)alkenyl, or a pharmaceutically acceptable salt thereof, that is effective in reducing nicotine addiction or aiding in the cessation or lessening of tobacco use.
The present invention also relates to a method for treating a disorder or condition selected from inflammatory bowel disease (including but not limited to ulcerative colitis, pyoderma gangrenosum and Crohn""s disease), irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, celiac sprue, pouchitis, vasoconstriction, anxiety, panic disorder, depression, bipolar disorder, autism, sleep disorders, jet lag, amyotrophic lateral sclerosis (ALS), cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrhythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supranuclear palsy, chemical dependencies and addictions (e.g., dependencies on, or addictions to nicotine (and/or tobacco products), alcohol, benzodiazepines, barbiturates, opioids or cocaine), headache, migraine, stroke, traumatic brain injury (TBI), obsessive-compulsive disorder (OCD), psychosis, Huntington""s chorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multi-infarct dementia, age-related cognitive decline, epilepsy, including petit mal absence epilepsy, senile dementia of the Alzheimer""s type (AD), Parkinson""s disease (PD), attention deficit hyperactivity disorder (ADHD) and Tourette""s Syndrome in a mammal, comprising administering to a mammal in need of such treatment an amount of a compound of the formula 
where R19 is defined above, or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder or condition.
This invention also relates to the pharmaceutically acceptable acid addition salts of the compounds of formula I. Examples of pharmaceutically acceptable acid addition salts of the compounds of formula I are the salts of hydrochloric acid, p-toluenesulfonic acid, fumaric acid, citric acid, succinic acid, salicylic acid, oxalic acid, hydrobromic acid, phosphoric acid, methanesulfonic acid, tartaric acid, malic acid, di-p-toluoyl tartaric acid, and mandelic acid, as well salts formed from other acids known to those of skill in the art to form pharmaceutically acceptable acid addition salts to basic compounds. Other possible acid addition salts are, e.g., salts containing pharmaceutically acceptable anions, such as the hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, and pamoate (i.e., 1.1xe2x80x2-methylene-bis-(2-hydroxy-3-naphthoate) salts).
The present invention also relates to methods for the preparation of the novel compounds of formula I. The invention is directed to a process for the preparation of a compound of formula IA: 
wherein R10 is defined above, comprising the step of reacting a compound of formula VI 
wherein Q is a nitrogen protecting group, with a compound of formula XXIIB: 
wherein R20 and R21 are each independently (C1-C6)alkyl, and wherein R10 is defined above; and
(ii) removing the protecting group Q.
The nitrogen protecting group Q may be chosen from suitable groups known to those of skill in the art including xe2x80x94COCF3, xe2x80x94COCCl3, xe2x80x94COOCH2CC3, xe2x80x94COO(C1-C6)alkyl and xe2x80x94COOCH2C6H5. These groups may be added or removed by methods described for each in T. W. Greene and G. M. Wuts, Protective Groups in Organic Synthesis (John Wiley and Sons, New York, 1991). Preferably, the nitrogen protecting group Q is a trifluoroacetyl or a t-butoxycarbonyl group.
The invention also relates to a process for the preparation of a compound of formula IB 
wherein R10 and R17 are defined above, comprising the steps of
(i) of reacting a compound of formula VI: 
xe2x80x83wherein Q is a nitrogen protecting group, with a compound of formula XXIIB: 
xe2x80x83wherein R20 and R21 are each independently (C1-C6)alkyl, and wherein R10 is defined above; and
(ii) allowing the product of step (i) to react with a compound of the formula R17Z, wherein R17 is defined above, and Z is a leaving group, in the presence of a base;
(iii) removing the protecting group Q.
Preferably, in this method to prepare IB the leaving group is selected from the group consisting of halo, halosulfonate, mesylate and tosylate, and the base is an alkali metal hydride, hydroxide or carbonate. Preferably, the protecting group Q is a trifluoroacetyl or a t-butoxycarbonyl group.
The invention also relates to another process for the preparation of a compound of formula IB: 
wherein R10 and R17 are defined above, comprising the steps of
(i) of reacting a compound of formula XXIIIA: 
xe2x80x83wherein Q is a nitrogen protecting group, with a compound of formula XXIIB: 
xe2x80x83wherein R20 and R21 are each independently (C1-C6)alkyl, and wherein R10 is defined above; and
(iii) removing the protecting group Q.
Preferably, in this method to prepare IB, the protecting group Q is a trifluoroacetyl or a t-butoxycarbonyl group.
The invention is also directed to a process for preparing a compound of formula IC 
wherein R10 and R17 are as defined above, comprising the steps of
(i) allowing a compound of formula VI: 
xe2x80x83wherein Q is a nitrogen protecting group, to react with a compound of formula 
xe2x80x83wherein Y is an alkali metal or alkaline earth metal cation; or a compound of formula 
xe2x80x83wherein R10 and R17 are as defined above; and
(ii) removing the protecting group Q.
The protecting group Q is preferably a trifluoroacetate group or a t-butoxycarbonyl group. Preferably, step (i) is conducted in a polar solvent, more preferably, water, THF, DMF, DMSO, a mixture of water and any of THF, DMF or DMSO. In addition, the processes to make each of compounds IA, IB and IC, preferably comprise the further step of reducing the nitro groups of a compound of formula IIC: 
wherein Q is a nitrogen protecting group to form a compound of formula VI 
More preferably, the reduction is conducted in the presence of hydrogen gas employing a palladium catalyst. Preferably, the protecting group Q is a trifluoroacetyl or a t-butoxycarbonyl group.
The invention is also directed to a process for the preparation of a compound of formula IE: 
wherein R10 is defined above, comprising the steps of
(i) reducing the nitro group of a compound of formula VIIIA 
xe2x80x83wherein Q is a nitrogen protecting group;
(ii) allowing the amino product to react with an acid chloride of the formula R10COCl or an acid anhydride of the formula (R10CO)2O wherein R10 is (C1-C6)alkyl, or a compound of the formula R10C((C1-C6)alkoxy)3;
(iii) removing the protecting group Q.
Preferably, in this process to prepare IE, the reduction of step (i) is conducted by hydrogenation with a palladium or platinum catalyst. Preferably, the protecting group Q is a trifluoroacetyl or a t-butoxycarbonyl group.
The invention is further related to a process for the preparation of a compound of formula IF: 
wherein R10 is as defined above; comprising the steps of
(i) allowing a compound of formula XA: 
xe2x80x83wherein R10 is as defined above, and Q is a nitrogen protecting group, to react with Lawesson""s reagent;
(ii) allowing the product of step (i) to react with potassium ferricyanide and sodium hydroxide;
(iii) removing the protecting group Q.
Preferably, the protecting group Q is a trifluoroacetyl or a t-butoxycarbonyl group.
The invention also relates to a process for preparing compounds the formula: 
wherein R2 and R3 are defined above; comprising the steps of
(i) subjecting a compound of formula XIIIB: 
xe2x80x83to ozonolysis conditions;
(ii) partially reducing the resulting ozonide product of step (i) to a dialdehyde or product of equivalent oxidation state;
(iii) allowing the product of step (ii) to react with an arylmethylamine; and
(iv) removing the arylmethyl group.
The ozonolysis conditions used may be any of those known to those of skill in the art. Preferably, the ozonolysis conditions are ozone in methanol or dichloromethane, preferably methanol. In step (ii), the reduction of the ozonolysis product or ozonide is preferably conducted by hydrogenation, e.g., in the presence of hydrogen gas and a platinum or palladium catalyst with or without carbon/charcoal. The arylmethylamine employed in step (iii) is benzylamine, 4-methoxybenzylamine or 3,4-dimethoxybenzylamine, preferably benzylamine, and is preferably added in the presence of an acid catalyst, preferably formic acid. The removal of the arylmethyl group in step (iv) is preferably a hydrogenolysis reaction conducted, e.g., in the presence of hydrogen gas and a platinum or palladium catalyst with or without carbon/charcoal, and in the presence of an acid catalyst.
The invention also relates to a novel process for the preparation of a compound of formula 
comprising the steps of
(i) hydrogenating a compound having the formula XXVIII or XXVIIIxe2x80x2: 
xe2x80x83wherein R2 and R3 are defined above;
(ii) cyclizing the amine-ester compound of formula XXIX 
xe2x80x83obtained from step (i) to form a lactam ring compound of formula XXX 
(iii) reducing the carbonyl moiety.
The preferred starting material in step (i) is the trimethylsiloxy compound. The hydrogenation of step (i) is preferably conducted with a palladium or platinum catalyst under hydrogen gas, preferably in the presence of an acid catalyst. The lactam formation of step (ii) is preferably performed in the presence of a base, preferably an alkoxyalkalide compound in a nonaqueous protic solvent, more preferably sodium tert-butoxide in methanol. The reduction of step (iii) is preferably performed in the presence of a borane tetrahydrofuran complex, diborane, borane dimethysulfide complex, lithium aluminum hydride or a combination of sodium borohydride and boron trifluoride, more preferably a combination of sodium borohydride and boron trifluoride.
Except where otherwise stated, R1 through R19, m, P and Pxe2x80x2, and structural formula I in the reaction schemes and discussion that follow are defined as above. Schemes 1-10, below, illustrate methods of synthesizing compounds of the formula I. 
Referring to Scheme 1, the starting material of formula III is reacted with trifluoroacetic anhydride, in the presence of pyridine, to form the compound of formula IV. This reaction is typically conducted in methylene chloride at a temperature from about 0xc2x0 C. to about room temperature. Other methods of generating a trifluoroacetate protecting group that may be used are recognized by those of skill in the art.
The compound of formula IV is then converted into the dinitro derivative of formula IIA by the following process. The compound of the formula IV is added to a mixture of 4 or more equivalents of trifluoromethanesulfonic acid (CF3SO2OH) and 2 to 3 equivalents of nitric acid, in a chlorinated hydrocarbon solvent such as chloroform, dichloroethane (DCE) or methylene chloride. The resulting mixture is allowed to react for about 5 to 24 hours. Both of the foregoing reactions are generally conducted at a temperature ranging from about xe2x88x9278xc2x0 C. to about 0xc2x0 C. for about 2 hours, and then allowed to warm to room temperature for the remaining time.
Reduction of the compound of formula IIA, using methods well known to those of skill in the art, yields the compound of formula IIB. This reduction can be accomplished, for example, using hydrogen and a palladium catalyst such as palladium hydroxide or palladium on carbon and running the reaction in methanol at about room temperature. The steps of Scheme 1 can also be performed with a nitrogen-protecting group, other than an a trifluoroacetyl group, that would be deemed suitable by those of skill in the art. Other suitable nitrogen protecting groups that can be used in the procedures described throughout this document include xe2x80x94COCF3, xe2x80x94COCCl3, xe2x80x94COOCH2CCl3, xe2x80x94COO(C1-C6)alkyl and xe2x80x94COOCH2C6H5. These groups may be added or removed by methods described for each in T. W. Greene and G. M. Wuts, Protective Groups in Organic Synthesis (John Wiley and Sons, New York, 1991).
Referring to Scheme 2, the compound of formula IIA is converted into the corresponding compound wherein the trifluoroacetyl protecting group is replaced by a t-Boc protecting group (VIA) by reacting it first with an alkali metal or alkaline earth metal (or ammonium) hydroxide or carbonate, and then reacting the isolated product from the foregoing reaction with di-t-butyidicarbonate. Although t-Boc is used in this instance, other appropriate nitrogen-protecting groups known to those of skill in the art may be used. The reaction with the alkali or alkaline earth metal (or ammonium) hydroxide or carbonate is generally carried out in an aqueous alcohol, dioxane or tetrahydrofuran (THF) at a temperature from about room temperature to about 70xc2x0 C., preferably at about 70xc2x0 C., for about one to about 24 hours. The reaction of the isolated, unprotected amine or an acid addition salt of such amine, from the above reaction with di-t-butyldicarbonate is preferably carried out in a solvent such as THF, dioxane or methylene chloride at a temperature from about 0xc2x0 C. to about room temperature. This reaction may or may not be conducted in the presence of a base. When the reactant is a salt of the amine, use of a base is preferred. The resulting compound of formula VIA can be converted into the corresponding diamino derivative of formula VIB using the procedure described above for converting the dinitro compound of formula IIA into the corresponding diamino compound of formula IIB, or other generally accepted nitro group reduction methods known to those of skill in the art, e.g., zinc-, tin-, or iron-mediated reductions, etc.
The conversion of the compound of formula VIB into the desired compound of the formula VII can be accomplished by reacting the compound of formula VIB with a compound of the formula XXIIA 
wherein R10 is hydrogen, (C1-C6)alkyl optionally substituted with from one to seven fluorine atoms, aryl-(C0-C3)alkyl wherein said aryl is selected from phenyl and naphthyl, or heteroaryl-(C0-C3)alkyl wherein said heteroaryl is selected from five to seven membered aromatic rings containing from one to four heteroatoms selected from oxygen, nitrogen and sulfur, and wherein each of the foregoing aryl and heteroaryl groups may optionally be substituted with one or more substituents, preferably from zero to two substituents, independently selected from (C1-C6)alkyl optionally substituted with from one to seven fluorine atoms, (C1-C6)alkoxy optionally substituted with from one to seven fluorine atoms and cyano. The preferred solvent for this reaction is a 10:1 mixture of ethanol/acetic acid. The reaction temperature can range from about 40xc2x0 C. to about 100xc2x0 C. It is preferably about 60xc2x0 C. Other appropriate solvents include acetic acid, ethanol and isopropanol.
Alternate methods of preparing compounds of the formula VII the compound of formula VIB are described by Segelstein et al., Tetrahedron Lett., 1993, 34, 1897.
Removal of the t-Boc protecting group from the compound of formula VII yields corresponding compound of formula IA. The protecting group can be removed using methods well known to those of skill in the art. For example, the compound of formula VII can be treated with an anhydrous acid such as hydrochloric acid, hydrobromic acid, methanesulfonic acid, or trifluoroacetic acid, preferably hydrochloric acid in ethyl acetate, at a temperature from about 0xc2x0 C. to about 100xc2x0 C., preferably from about room temperature to about 70xc2x0 C., for about one to 24 hours.
The compound of formula VII can be converted into the corresponding compound of formula IB by reacting it with a compound of the formula R17Z, wherein R17 is defined as R10 is defined above, and Z is a leaving group such as a halo or sulfonate (e.g., chloro, bromo, mesylate or tosylate), in the presence of a base such as an alkali metal hydride, hydroxide or carbonate, preferably potassium hydroxide, in a polar solvent such as water, dimethylsulfoxide (DMSO), THF or DMF, preferably a mixture of DMSO and water, and then removing the protecting group as described above. The reaction with R17Z is generally carried out at a temperature from about room temperature to about 100xc2x0 C., preferably at about 50xc2x0 C., for about five hours.
Scheme 3 illustrates an alternate method of preparing compounds of the formula IB from the compound of formula VIA. This method is the preferred method of making compounds of the formula IB wherein R17 is a bulky group such as an aryl or heteroaryl containing group, or when R17 can not be attached, as illustrated in Scheme 2, by alkylation or aryl substitution methods. Referring to Scheme 3, the compound of formula VIA is reacted with the appropriate compound of formula R17NH2 in a polar solvent such as THF, DMF or DMSO, preferably THF, at a temperature from about room temperature to about 100xc2x0 C., preferably at the reflux temperature, for about four to eighteen hours. The resulting compound of formula XXIII is then converted into the corresponding compound of the formula XXIV by reducing the nitro group to an amino group using methods well known to those of skill in the art. Such methods are referred to above for the conversion of the compounds of the formula IIA into a compound of the formula IIB in Scheme 1, and exemplified in experimental Examples 12B and 18B. Closure to the imidazole ring to form the corresponding compound of formula XXV can then be accomplished by reacting the compound of formula XXIV from the above reaction with a compound of the formula XXIIA: 
wherein R10 is defined as above, as described above for converting compounds of the formula VIB into those of the formula VII.
Removal of the protecting group from the compound of formula XXV yields the corresponding compound of formula IB. This can be accomplished using methods well known in the art, for example, as described above for forming compounds of the formula IA from the corresponding compounds of the formula VII.
Scheme 4 illustrates a method of preparing compounds of the formula IC, wherein R10 and R17 are as defined above. Referring to Scheme 4, the compound of formula VIB, or analogously formula IIB in Scheme I, is reacted with a compound of the formula 
(sodium bisulfite ethane dione addition adduct) in water or another polar solvent such as THF, DMF or DMSO, preferably a mixture of water and a water miscible solvent such as THF, for about one to four hours. The reaction temperature can range from about 40xc2x0 C. to about 100xc2x0 C., and is preferably at about the reflux temperature.
Alternatively, the compound of formula VIB can be reacted with a compound of the formula 
(double condensation reaction) in a polar solvent such as THF, water, or acetic acid, preferably a mixture of water and THF. This reaction is typically carried out at a temperature from about 40xc2x0 C., to about 100xc2x0 C., preferably at the reflux temperature, for about two to four hours. The desired quinoxoline of formula IC can then be formed by deprotecting the compound formed in either of the foregoing reactions, using the method described above for converting a compound of the formula VII into one of the formula IA. Alternatively, in place of compound VIB in Scheme 4, the compound IIB of Scheme 1 may be used analogously in this procedure with deprotection/reprotection as outlined in Scheme 2 (i.e., the process of transforming IIA to VIA) in order to arrive at ultimately the compound IC. In general, alternative nitrogen protection groups are equally suited to the procedure of Scheme 4.
Scheme 5 illustrates a method of preparing compounds of the formula I wherein R2 and R3, together with the benzo ring to which they are attached, form a benzoxazole ring system. Such a compound, wherein R1 is hydrogen, is depicted in Scheme 5 as chemical formula IE. Referring to Scheme 5, the compound of formula XXII, wherein Y is nitro, halo, trifluoromethanesulfonate or a diazonium salt, is reacted with potassium acetate or another alkali or alkaline earth metal carboxylate in a solvent such as dimethylsulfoxide (DMSO), DMF or acetonitrile, preferably DMSO. This reaction is generally allowed to run for about 12-24 hours. Appropriate reaction temperatures range from about 70xc2x0 C. to about 140xc2x0 C. Approximately 100xc2x0 C. is preferred.
The above reaction yields the compound of formula VIII, which can then be converted into the desired compound having formula IE by the following procedure. First, the compound of formula VII is reduced by reaction with hydrogen and a palladium or platinum catalyst such as palladium hydroxide in methanol at a temperature from about 0xc2x0 C. to about 70xc2x0 C., preferably at about room temperature, to form the corresponding amino derivative. The product of this reaction is then reacted with an acid chloride of the formula R10COCl or an acid anhydride of the formula (R10CO)2O wherein R10 is (C1-C6)alkyl, or a compound of the formula R10C(OC2H5)3, in an appropriate inert solvent such as decalin, chlorobenzene or xylenes. A mixture of xylenes is preferred. This reaction is typically conducted at a temperature from about 120-150xc2x0 C., preferably at about 140xc2x0 C. When R10COCl is used as a reactant, it is preferable to add a stoichiometric amount of triethylamine (TEA) or another organic tertiary amine base and a catalytic amount of pyridinium p-toluenesulfonic acid or pyridinium p-toluenesulfonate (PPTs) to the reaction mixture. When R10C(OC2H5)3 is used as a reactant, it is preferable to add a catalytic amount of PPTs to the reaction mixture.
Removal of the trifluoroacetyl nitrogen protecting group yields the desired compound of the formula IE. This can be accomplished using methods well known to those of skill in the art, for example, reacting the protected compound with a lower alkanol and an aqueous alkali or alkaline earth metal (or ammonium) hydroxide or carbonate, aqueous sodium carbonate, at a temperature from about 50xc2x0 C. to about 100xc2x0 C., preferably at about 70xc2x0 C., for about two to six hours.
Scheme 6 illustrates the preparation of compounds of the formula I wherein R1 is hydrogen and R2 and R3, together with the benzo ring to which they are attached, form a benzothiazole ring system. Referring to Scheme 6, the compound of formula III is reacted with trifluoroacetic anhydride to form the corresponding compound wherein the ring nitrogen is protected by a trifluoroacetyl group, and the resulting nitrogen protected compound is then reacted with two equivalents of trifluoromethanesulfonic anhydride and one equivalent of nitric acid to form the corresponding compound of formula IX, wherein there is a single nitro substituent on the benzo ring. The reaction with trifluoroacetic acid is typically conducted in the presence of pyridine. Both of the above reactions are typically conducted in a reaction inert solvent such as a chlorinated hydrocarbon solvent, preferably methylene chloride, at a temperature from about 0xc2x0 C. to about room temperature, preferably at about room temperature.
The above transformation can also be accomplished using other nitration methods known to those skill in the art. Reduction of the nitro group to an amine group can be accomplished as described above to provide a compound of the formula IXxe2x80x2.
The compound of formula IXxe2x80x2 is then reacted with a carboxylic acid halide or anhydride of the formula R10COX or (R10CO)2O, wherein X is halo and R10 is hydrogen or (C1-C6)alkyl, and pyridine, TEA or another tertiary amine base, to form a compound of the formula X, which can then be converted to the desired compound having formula XI by reacting it with Lawesson""s reagent: 
The reaction with R10COX, wherein X is halo, or (R10CO)2O is generally carried out at a temperature from about 0xc2x0 C. to about room temperature, preferably at about room temperature. The reaction with Lawesson""s reagent is generally carried out in a reaction inert solvent such as benzene or toluene, preferably toluene, at a temperature from about room temperature to about the reflux temperature of the reaction mixture, preferably at about the reflux temperature.
Closure to the benzothiazole ring and nitrogen deprotection to form the desired compound of formula IF can be accomplished by reacting the compound of formula XI with potassium ferricyanide and sodium hydroxide in a mixture of water and methanol (NaOH/H2O/CH3OH), at a temperature from about 50xc2x0 C. to about 70xc2x0 C., preferably at about 60xc2x0 C. for about 1.5 hours.
Scheme 7 illustrates a method of preparing the compound of formula III, which is used as the starting material for the process of Scheme 1, or a compound of the formula IG, wherein R2 and R3 form a ring (labeled xe2x80x9cAxe2x80x9d in the Scheme), as defined above in the definition of compounds of the formula I. Referring to Scheme 7, the compound of formula XII, wherein X1 and X2 are selected, independently, from chloro, fluoro, bromo and iodo, but where at least one of X1 and X2 is Br- or I-, reacted with cyclopentadiene, in the presence of magnesium metal, in a THF, dioxane or other ethereal solvent, at a temperature from about 40xc2x0 C. to about 100xc2x0 C., preferably at about the reflux temperature, to form a compound of the formula XIII. Reaction of the resulting compound of formula XIII with N-methylmorpholine-N-oxide (NMO) and osmium tetroxide in acetone at about room temperature yields the corresponding compound of the formula XIIIA.
The compound having formula XIIIA is then converted into the corresponding compound of formula XIV using the following procedure. First, the compound of formula XIIIA is reacted with sodium periodate in a mixture of a chlorinated hydrocarbon, preferably dichloroethane (DCE), and water, or with lead tetraacetate in a chlorinated hydrocarbon solvent, at a temperature from about 0xc2x0 C. to about room temperature, to generate a dialdehyde or glycal intermediate. The product of this reaction is then reacted with benzylamine and sodium triacetoxyborohydride in a chlorinated hydrocarbon solvent at a temperature from about 0xc2x0 C. to about room temperature, preferably at about room temperature, to form the desired compound of formula XIV. Removal of the benzyl group from the compound of formula XIV yields the compound of formula III (when ring A is absent) or IG, (when ring A is present). This can be accomplished using methods well known to those of skill in the art, for example, optionally reacting the free base with one equivalent of acid, e.g., hydrochloric acid, (to form the corresponding acid addition salt), followed by hydrogenolysis and palladium hydroxide in methanol at about room temperature.
In the reductive animation step described above and throughout this document, alternatives to benzyl amine, such as ammonia, hydroxylamine, alkoxy amines, methyl amine, allyl amine, and substituted benzylamines (e.g., diphenylmethyl amine and 2- and 4-alkoxy substituted benzyl amines) can also be used. They can be used as free bases, or as their salts, preferably their acetate salts, and can be subsequently removed by methods described for each in T. W. Greene and G. M. Wuts, Protective Groups in Organic Synthesis (John Wiley and Sons, New York 1991).
The procedure of Scheme 7 can also be used to prepare compounds of the formula I wherein R2 and R3 do not form a ring and are not both hydrogen, by replacing the starting material of formula XII with the appropriate compound having the formula XIIxe2x80x2 
Alternatively, a compound of formula XIII can be converted, via methods described below and in Scheme 8, to compounds of formula XIV or formula IG or formula III.
An alternative means of preparing a compound of formula IIIxe2x80x2, or as appropriate IGxe2x80x2, is illustrated in Scheme 7A. This process can be applied to produce compounds of compounds of formula I, where R1 is hydrogen, and R2 and R3 are as defined above, with the exception of when R2 and R3 are hydroxy, amino, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, xe2x80x94C(xe2x95x90O)R13, or xe2x80x94(C1-C6)alkylene-C(xe2x95x90O)R13.
Referring to Scheme 7A, step 1 of is an esterification of a carboxylic acid. A carboxylic acid of formula XXVI is treated with a Lewis acid catalyst such as boron trifluoride, or with an acid catalyst such as sulfuric acid, hydrochloric acid, p-toluenesulfonic acid, methane sulfonic acid, trifluoroacetic acid, or hydrobromic acid, preferably sulfuric acid, in an alcohol solvent such as methanol, ethanol, propanol, butanol, pentanol, or hexanol, preferably methanol, at a temperature between 25 and 120xc2x0 C., preferably 65xc2x0 C., for a period of 30 minutes to 24 hours, preferably 4 hours, to afford a compound of formula XXVIIA.
Step 2 of Scheme 7A is a cyanohydrin formation. A ketone of formula XXVIIA is treated with a Lewis acid catalyst such as zinc iodide, zinc triflate, trimethylsilyl triflate, trimethylsilyl iodide, aluminum chloride, tin (II) chloride, or trimethyl aluminum, preferably zinc iodide, or with catalytic potassium cyanide and 18-crown-6, and trimethylsilyl cyanide, in a solvent such as acetonitrile, toluene, methylene chloride, ethyl acetate, isopropyl acetate, methyl-tert-butyl ether, or tetrahydrofuran, preferably a mixture of acetonitrile and toluene, at a temperature between 0 and 100xc2x0 C., preferably at 50xc2x0 C., for a period of time between 1 and 24 hours, preferably 5 hours, to afford a compound of formula XXVIIIA.
Step 3 of Scheme 7A is a hydrogenolysis reaction. A nitrile of formula XXVIIIA is treated with an acid catalyst such as p-toluenesulfonic acid, methane sulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, or trifluoroacetic acid, preferably p-toluenesulfonic acid, and a palladium catalyst such as palladium on carbon or palladium hydroxide on carbon, preferably palladium hydroxide on carbon, in a solvent such as methanol, ethanol, isopropanol, butanol, propanol, ethyl acetate, isopropyl acetate, or toluene, preferably methanol, under a hydrogen pressure of 15 to 100 psi, preferably 50 psi, for a time period between 2 and 72 hours, preferably 24 hours, to afford a compound of formula XXIXA.
Step 4 of Scheme 7A is an amide formation. An amine of formula XXIXA is treated with a base such as sodium tert-butoxide, sodium methoxide, sodium ethoxide, sodium hydroxide, potassium tert-butoxide, potassium methoxide, potassium ethoxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, triethylamine, methylimidazole, lutidine, pyridine, methylmorpholine, ethylmorpholine, or diisopropylethylamine, preferably sodium tert-butoxide, in a solvent such as methanol, ethanol, isopropanol, ethyl acetate, acetonitrile or toluene, preferably methanol, at a temperature between 0 and 120xc2x0 C., preferably 65xc2x0 C., for a time period between 30 minutes and 72 hours, preferably 2 hours, to afford a compound of formula XXX.
Step 5 of Scheme 7A is a reduction of an amide. An amide of formula XXX is treated with a reducing agent such as borane tetrahydrofuran complex, diborane, borane dimethylsulfide complex, lithium aluminum hydride, or a combination of sodium borohydride and boron trifluoride, preferably a combination of sodium borohydride and boron trifluoride, in a solvent such as tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane, diisopropyl ether, 1,4-dioxane, or methyl-tert-butyl ether, preferably tetrahydrofuran, at a temperature between 0 and 80xc2x0 C., preferably 50xc2x0 C., for time period between 1 and 24 hours, preferably 5 hours. The product is isolated by crystallization as a salt of an acid such as p-toluenesulfonic acid, methane sulfonic acid, hydrochloric acid, oxalic acid, citric acid or acetic acid, preferably p-toluenesulfonic acid, in a solvent such as isopropanol, hexane, acetone, ethyl acetate, methyl ethyl ketone, or toluene, preferably isopropanol, to afford the salt form of compound of formula IG or III.
Scheme 8, 9 and 10 illustrate methods of preparing compounds of the formula I wherein R1 is hydrogen, and R2 and R3 represent a variety of different substituents, as defined above, but do not form a ring.
Scheme 8 illustrates a variation of the process shown in Scheme 7, which can be used to make a compound identical to that of formula III except that the benzo ring is substituted with a fluoro group, an alkoxy group or any other suitable R2 and/or R3 group (R18 in Scheme 8). This compound is depicted in Scheme 8 as chemical structure 1H. Referring to Scheme 8, where, for example, R18 is F, 1,3-difluorobenzene is reacted with a strong base such as an alkali metal dialkylamine or an alkali metal alkyl (or aryl) in an ethereal solvent such as ethyl ether or THF, at a temperature below xe2x88x9250xc2x0 C., followed by quenching with iodine or N-iodosuccinamide, to form 1,3-difluoro-2-iodobenzene. The compound 1,3-difluoro-2-iodobenzene (structural formula XVI in Scheme 8) is then converted into the compound of formula IH by a series of reactions (represented in Scheme 8 as XVIxe2x86x92XVIIxe2x86x92XVIIIxe2x86x92XIXxe2x86x92IH) that are analogous to the series of reactions described above and illustrated in Scheme 7 or Scheme 8A for converting compounds of the formula XIII into those of the formula IG or III. Conversion of the compound of formula XVI into the compound of formula XVII can also be accomplished by treating a mixture of the compound of formula XVI and cyclopentadiene with an alkyl lithium reagent, preferably n-butyl lithium, in an inert hydrocarbon solvent such as petroleum ether, toluene or methyl cyclohexane, at a temperature from about xe2x88x9220xc2x0 C. to about room temperature, preferably at about 0xc2x0 C. This procedure is equally effective to effect the conversion as set forth in Scheme 7 with or without the R18 group present.
The compound of formula IH can then be converted into the corresponding nitrogen protected derivative of formula XX, using the methods described above for synthesizing the compound of formula IV in Scheme 1. Nitration of the compound of formula XX using the method described above for preparing the compound of formula IX in Scheme 6, yields the compound of formula XXI wherein the benzo ring is substituted with both a fluoro and nitro group, an alkoxy group and nitro group, or an R18 substituent and a nitro group. The compound of formula XXI can be used to make a variety of compounds of the formula I wherein one of R2 and R3 is fluoro, using methods that are well known to those of skill in the art, for example, by first converting the nitro group to an amino group, converting the amino group to a variety of other substituents, as illustrated in Scheme 10, and then removing the nitrogen protecting group.
The compound of formula XXI acts as a regioisomeric functional equivalent of the compounds having formulas IIA, VIA and XXII, in that the fluorine atom of formula XXI reacts similarly to the nitro and Y groups of formula IIA, VIA, and XXII, and thus can be subjected to the same series of reactions as those described above for the latter three compounds, providing an alternate means for preparing the products of such reactions. Similarly, the alkoxy group of formula XXI (R18=alkoxy) may be converted into a hydroxyl group before or after introduction of the nitro group, and then converted to isomeric products as described above. Also, the trifluoromethanesulfonate ester of such hydroxy derivative can act as a Y-group as described.
Preparation of compounds of formula I where R2=xe2x80x94O(C1-C6)alkyl, (C1-C6) alkyl or aryl wherein aryl is defined as above in the definition of formula I, and R3 is H or one of the other substituents described above in the definition of formula I, can be prepared as described above and illustrated in Scheme 8 by replacing one of the fluorine atoms of the compound of formula XV with xe2x80x94Oxe2x80x94(C1-C6)alkyl, (C1-C6)alkyl or aryl, respectively.
Scheme 8A illustrates an alternative procedure for obtaining compounds of formula I, where R2 and R3 are as defined above, with the exception of (C2-C6)alkenyl, (C2-C6)alkynyl or nitro (IHxe2x80x2, as depicted). Step 1 of Scheme 8A is an oxidation followed by a reductive amination. A benzonorbornadiene derivative of formula XVIIxe2x80x2 is first treated with ozone until the solution develops a blue color between 0xc2x0 C. and xe2x88x9278xc2x0 C., preferably xe2x88x9278xc2x0 C., in a solvent such as methanol, or dichloromethane, preferably methanol. The ozonide formed is reduced by hydrogenolysis between xe2x88x9278xc2x0 C. and room temperature, preferably between 0xc2x0 C. and room temperature, with platinum or palladium catalyst such as platinum oxide, platinum on carbon, palladium on carbon, or palladium hydroxide on carbon, preferably 5% platinum on carbon, for a period of time between 5 minutes and 6 hours, preferably 1 hour, under a hydrogen atmosphere between 15 and 100 psi, preferably between 30 and 50 psi. Next, an arylmethylamine, such as benzylamine, 4-methoxybenzylamine, or 3,4-dimethoxybenzylamine, preferably benzylamine is added to the reaction mixture at room temperature with an acid catalyst such as formic acid, acetic acid, p-toluenesulfonic acid, oxalic acid, or hydrochloric acid, preferably formic acid, and hydrogenolysis is resumed for a period of time between 1 and 12 hours, preferably 4 hours, at a hydrogen pressure between 15 and 100 psi, preferably 50 psi, to afford a compound of formula XIXxe2x80x2, where Ar is an aryl group.
Step 2 of Scheme 8A is a hydrogenolysis reaction. A compound of formula II is treated with an acid such as p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, acetic acid, formic acid, or methane sulfonic acid, preferably p-toluenesulfonic acid, and a palladium catalyst such as palladium hydroxide on carbon or palladium on carbon, preferably palladium hydroxide on carbon, in a solvent such as methanol, ethanol, isopropanol, ethyl acetate, or methyl acetate, preferably methanol, under a hydrogen pressure between 15 and 100 psi, preferably 50 psi, at a temperature between room temperature and 600xc2x0 C., preferably 40xc2x0 C., for a period of time between 1 and 48 hours, preferably 15 hours. The product is crystallized as a salt depending on which acid catalyst is used in a solvent such as isopropanol, hexane, acetone, ethyl acetate, methyl ethyl ketone, or toluene, preferably in a mixture of isopropanol and hexane, to afford a compound of formula IHxe2x80x2.
Scheme 9 illustrates methods of preparing compounds of the formula I wherein: (a) R1 is hydrogen and R2 is R7R8NO2Sxe2x80x94; (b) R1 and R2 are both chloro; and (c) R1 is hydrogen and R2 is R13C(xe2x95x90O)xe2x80x94. These compounds are referred to in Scheme 9, respectively, as compounds of formulas IJ, IK and IL.
Referring to Scheme 9, compounds of the formula IJ can be prepared by reacting the compound of formula IV with two or more equivalents of a halosulfonic acid, preferably chlorosulfonic acid, at a temperature from about 0xc2x0 C. to about room temperature. Reaction of the chlorosulfonic acid derivative so formed with an amine having the formula R7R8NH, wherein R7 and R8 are defined as above, followed by removal of the nitrogen protecting group, yields the desired compound having formula IJ.
Compounds of the formula IK can be prepared by reacting the compound of formula IV with iodine trichloride in a chlorinated hydrocarbon solvent, followed by removal of the nitrogen protecting group. The reaction with iodine trichloride is typically carried out at a temperature from about 0xc2x0 C. to about room temperature, and is preferably carried out at about room temperature. In a similar fashion, the analogous mono- or di-brominated or mono- or di-iodinated compounds can be prepared by reacting the compound of IV with N-iodosuccinamide or N-bromosuccinimide in a trifluoromethanesulfonic acid solvent, followed by removal of the nitrogen protecting group as described above.
Reaction of the compound of IV with an acid halide of the formula R13COCl or an acid anhydride of the formula (R13CO)2O, with or without a reaction inert solvent such as a chlorinated hydrocarbon solvent, preferably methylene chloride, in the presence of Lewis acid such as aluminum chloride, at a temperature from about 0xc2x0 C. to about 100xc2x0 C., followed by nitrogen deprotection, yields the compound of formula IL. The reaction with the acid halide or anhydride can be carried out using other known Lewis acids or other Friedel-Crafts acylation methods that are known in the art.
The reactions described herein in which xe2x80x94NO2, xe2x80x94SO2NR7R8, xe2x80x94COR13, I, Br or Cl are introduced on the compound of formula IV, as depicted in Scheme 9 and described above, can be performed on any analogous compound wherein R2 is hydrogen, (C1-C6)alkyl, halo, (C1-C6)alkoxy or xe2x80x94NHCONR7R8, producing compounds of the formula I wherein R2 and R3 are defined as in the definition of compounds of the formula I above.
Compounds that are identical to those of the formula IL, but which retain the nitrogen protecting group, can be converted into the corresponding O-acyl substituted compounds, i.e., those wherein the xe2x80x94C(xe2x95x90O)R13 group of formula IL is replaced with a xe2x80x94Oxe2x80x94C(xe2x95x90O)R13 group, using Baeyer-Villiger processes well known to those skilled in the art. The resulting compounds can be partially hydrolyzed, as described in Example 35, to yield the corresponding hydroxy substituted compounds, and then alkylated to form the corresponding alkoxy substituted compounds. Also, as described in Example 36, such O-acyl substituted compounds can be used to prepare variably substituted benzisoxazoles.
Scheme 10 illustrates methods of making compounds of the formula I wherein: (a) R1 is hydrogen and R2 is chloro; (b) R1 is hydrogen and R2 is cyano; (c) R1 is hydrogen and R2 is amino; and (d) R1 is hydrogen and R2 is R13C(xe2x95x90O)N(H)xe2x80x94. These compounds are referred to in Scheme 10, respectively, as compounds of the formula IM, IN, IP and IQ.
Compounds of formula IM can be prepared from compounds of the formula IXxe2x80x2 by generation of a diazonium salt with, for instance, an alkali metal nitrite and strong mineral acid (e.g., hydrochloric acid, sulfuric acid, hydrobromic acid) in water, followed by reaction with a copper halide salt, such as copper (I) chloride. Nitrogen deprotection by the methods described above yields the desired compound of formula IM. Alternative methods for the generation of diazonium salts, as known and practiced by those of skill in the art, can also be used. The foregoing reaction is generally carried out by temperatures ranging from about 0xc2x0 C. to about 60xc2x0 C., preferably about 60xc2x0 C. for about 15 minutes to one hour.
Reaction of the diazodium salt, prepared as described above, with potassium iodide in an aqueous medium provides the analogous iodide derivative. This reaction is generally carried out at a temperature from about 0xc2x0 C. to about room temperature, preferably at about room temperature. The resulting compound, or its analogous N-tert-butylcarbonate protected form, can be used to prepare the corresponding cyano derivative by reaction with copper (I) cyanide and sodium cyanide in DMF, N,N-dimethylpropylurea (DMPU) or DMSO, preferably DMF, at a temperature from about 50xc2x0 C. to about 180xc2x0 C., preferably about 150xc2x0 C. Nitrogen deprotection as described above provides the desired compound of formula IM.
The above described iodide derivative can also be used to access a variety of other substituents such as aryl, acetylene and vinyl substituents, as well as the corresponding carbonyl esters and amides, by palladium and nickel catalyzed processes known to those of skill in the art, such as Heck, Suzuki and Stille couplings and Heck carbonylations. These compounds and others, wherein R2 is halo, alkyl, alkoxy, etc., may be similarly functionalized to generate compounds wherein R2 and R3 are as defined above.
Nitrogen deprotection of the compound of formula IXxe2x80x2 provides the compound of the formula IP. The compound of formula IXxe2x80x2 can be reacted with a acyl group having the formula R13COCl or (R13CO)2O using the methods described above, followed by nitrogen deprotection to provide compounds of the formula IQ. In a similar fashion, treatment of the protected amine with a compound having the formula R13SO2X, when X is chloro or bromo, followed by nitrogen deprotection, provides the corresponding sulfonamide derivative.
As noted above, suitable amine protecting groups that can be used, alternatively, in the procedures described throughout this document include xe2x80x94COCF3, xe2x80x94COCCl3, xe2x80x94COOCH2CCl3, xe2x80x94COO(C1-C6)alkyl and xe2x80x94COOCH2C6H5. These groups may be removed by methods described for each in Greene et al.""s Protective Groups in Organic Chemistry, referred to above. Instances where protecting groups would be modified under the reaction conditions, such as, e.g., a xe2x80x94COOCH2C6H5 group during nitration, still permit said procedures to operate as described with said modified protecting group. Modifying the order of protecting group incorporation and/or methods of functional group introduction or modification may also be applied where appropriate.
In each of the reactions discussed above, or illustrated in Schemes 1-10, above, pressure is not critical unless otherwise indicated. Pressures from about 0.5 atmospheres to about 5 atmospheres are generally acceptable, with ambient pressure, i.e., about 1 atmosphere, being preferred as a matter of convenience.
The compounds of the formula I and their pharmaceutically acceptable salts (hereafter xe2x80x9cthe active compoundsxe2x80x9d) can be administered via either the oral, transdermal (e.g., through the use of a patch), intranasal, sublingual, rectal, parenteral or topical routes. Transdermal and oral administration are preferred. These compounds are, most desirably, administered in dosages ranging from about 0.01 mg up to about 1500 mg per day, preferably from about 0.1 to about 300 mg per day in single or divided doses, although variations will necessarily occur depending upon the weight and condition of the subject being treated and the particular route of administration chosen. However, a dosage level that is in the range of about 0.001 mg to about 10 mg per kg of body weight per day is most desirably employed. Variations may nevertheless occur depending upon the weight and condition of the persons being treated and their individual responses to said medicament, as well as on the type of pharmaceutical formulation chosen and the time period and interval during which such administration is carried out. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effects, provided that such larger doses are first divided into several small doses for administration throughout the day.
The active compounds can be administered alone or in combination with pharmaceutically acceptable carriers or diluents by any of the several routes previously indicated. More particularly, the active compounds can be administered in a wide variety of different dosage forms, e.g., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, transdermal patches, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents. In addition, oral pharmaceutical compositions can be suitably sweetened and/or flavored. In general, the active compounds are present in such dosage forms at concentration levels ranging from about 5.0% to about 70% by weight.
For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc can be used for tablefting purposes. Solid compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar, as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration the active ingredient may be combined with various sweetening or flavoring agents, coloring matter and, if so desired, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.
For parenteral administration, a solution of an active compound in either sesame or peanut oil or in aqueous propylene glycol can be employed. The aqueous solutions should be suitably buffered (preferably pH greater than 8), if necessary, and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes. The oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
It is also possible to administer the active compounds topically and this can be done by way of creams, a patch, jellies, gels, pastes, ointments and the like, in accordance with standard pharmaceutical practice.
The effectiveness of the active compounds in suppressing nicotine binding to specific receptor sites is determined by the following procedure which is a modification of the methods of Lippiello, P. M. and Femandes, K. G. (in The Binding of L-[3H]Nicotine To A Single Class of High-Affinity Sites in Rat Brain Membranes, Molecular Pharm., 29, 448-54, (1986)) and Anderson, D. J. and Americ, S. P. (in Nicotinic Receptor Binding of 3H-Cystisine, 3H-Nicotine and 3H-Methylcarmbamylcholine In Rat Brain, European J. Pharm., 253, 261-67 (1994)).
Male Sprague-Dawley rats (200-300 g) from Charles River were housed in groups in hanging stainless steel wire cages and were maintained on a 12 hour light/dark cycle (7 a.m.-7 p.m. light period). They received standard Purina Rat Chow and water ad libitum.
The rats were killed by decapitation. Brains were removed immediately following decapitation. Membranes were prepared from brain tissue according to the methods of Lippiello and Fernandez (Molec Pharmacol, 29, 448-454, (1986) with some modifications. Whole brains were removed, rinsed with ice-cold buffer, and homogenized at 0xc2x0 in 10 volumes of buffer (w/v) using a Brinkmann Polytron(trademark), setting 6, for 30 seconds. The buffer consisted of 50 mM Tris HCl at a pH of 7.5 at room temperature. The homogenate was sedimented by centrifugation (10 minutes; 50,000xc3x97g; 0 to 4xc2x0 C. The supernatant was poured off and the membranes were gently resuspended with the Polytron and centrifuged again (10 minutes; 50,000xc3x97g; 0 to 4xc2x0 C. After the second centrifugation, the membranes were resuspended in assay buffer at a concentration of 1.0 g/100 mL. The composition of the standard assay buffer was 50 mM Tris HCl, 120 mM NaCl, 5 mM KCl, 2 mM MgCl2, 2 mM CaCl2 and has a pH of 7.4 at room temperature.
Routine assays were performed in borosilicate glass test tubes. The assay mixture typically consisted of 0.9 mg of membrane protein in a final incubation volume of 1.0 mL. Three sets of tubes were prepared wherein the tubes in each set contained 50 xcexcL of vehicle, blank, or test compound solution, respectively. To each tube was added 200 xcexcL of [3H]-nicotine in assay buffer followed by 750 xcexcL of the membrane suspension. The final concentration of nicotine in each tube was 0.9 nM. The final concentration of cytisine in the blank was 1 xcexcM. The vehicle consisted of deionized water containing 30 xcexcL of 1 N acetic acid per 50 mL of water. The test compounds and cytisine were dissolved in vehicle. Assays were initiated by vortexing after addition of the membrane suspension to the tube. The samples were incubated at 0 to 4xc2x0 C. in an iced shaking water bath. Incubations were terminated by rapid filtration under vacuum through Whatman GF/B(trademark) glass fiber filters using a Brande(trademark) multi-manifold tissue harvester. Following the initial filtration of the assay mixture, filters were washed two times with ice-cold assay buffer (5 m each). The filters were then placed in counting vials and mixed vigorously with 20 ml of Ready Safe(trademark) (Beckman) before quantification of radioactivity. Samples were counted in a LKB Wallach Rackbeta(trademark) liquid scintillation counter at 40-50% efficiency. All determinations were in triplicate.
Specific binding (C) to the membrane is the difference between total binding in the samples containing vehicle only and membrane (A) and non-specific binding in the samples containing the membrane and cytisine (B), i.e.,
Specific binding=(C)xe2x95x90(A)xe2x80x94(B).
Specific binding in the presence of the test compound (E) is the difference between the total binding in the presence of the test compound (D) and non-specific binding (B), i.e., (E)xe2x95x90(D)xe2x80x94(B). % Inhibition=(1-((E)/(C)) times 100.
The compounds of the invention that were tested in the above assay exhibited IC50 values of less than 10 xcexcM.
The following experimental examples illustrate, but do not limit the scope of, this invention.